Camptothecin is a vegetable alkaloid contained in plants such as Camptotheca acuminata of Chinese origin and a type I topoisomerase inhibitor. This selectively binds to the type I topoisomerase which forms a complex with DNA to stabilize its structure. As a result, it prevents the recombination of the cleaved DNA, and leads to the stop of the synthesis of DNA, thereby inducing the death of cells.
Camptothecin exhibits a high anti-tumor effect, and an anticancer agent of it had been developed in the 1960s. However, it was shown to have a strong toxicity causing bone-marrow suppression and hemorrhagic cystitis, and therefore its clinical test had been discontinued.
After that, topotecan and irinotecan had been developed as derivatives of camptothecin which have a better solubility in water, a stronger anti-tumor activity and a lower toxicity than those of camptothecin.
Topotecan exhibits its anti-tumor effect without metabolism, and 20-40% of its dose is excreted renally. Therefore, diarrhea which is its side effect is mild.
Irinotecan per se has an anti-tumor effect. It is metabolized in vivo by carboxyesterase to form a more active metabolite, 7-ethyl-10-hydroxycamptothecin (hereinafter, referred to as EHC), said metabolite exhibits a stronger anti-tumor effect. Moreover, the ratio of irinotecan and EHC in the form of lactone, which is biologically active, in plasma is higher than that of topotecan, and irinotecan and EHC has a long half-life.
The camptothecin derivatives are used for the treatment of many types of cancers in clinical use. Topotecan has been approved for the treatment of small cell lung cancer and the treatment of ovarian cancer pretreated with cancer chemotherapeutic agent(s). Irinotecan has been approved for the treatment of wide cancers, i.e., small cell lung cancer, non-small cell lung cancer, cervical cancer, ovarian cancer, stomach cancer (inoperable or recurrent), colon-rectal cancer (inoperable or recurrent), breast cancer (inoperable or recurrent), squamous cell cancer, and lymphatic malignancy (non-Hodgkin's lymphoma).
As one of camptothecin derivatives, Patent Literature 1 discloses a camptothecin derivative conjugated to a polymer. This polymer conjugate is obtained by ester binding a phenolic camptothecin compound to a copolymer of polyethylene glycol and a polymer having a side chain of carboxy group. The polymer conjugate has an in vivo sustained-release property and an excellent therapeutic effect on the basis of the binding of camptothecin compound via phenyl ester linkage which can be easily chemically cleaved. Further, the polymer conjugate forms a micelle and has an efficacy selective to tumors. It is expected to have a less side effect. Moreover, the polymer conjugate can release camptothecin compound without depending on enzyme(s). This suggests that the therapeutic effect of the polymer conjugate is not likely to be affected by the individual differences among patients.
Poly(ADP-ribose)polymerase (PARP) is the enzyme catalyzing polyADP-ribosyl action that adding ADP ribose residue to proteins by using oxidative NAD (nicotinamide adenine dinucleotide) as a substrate to polymerize them. PARP senses the cleavage of single-stranded DNA, and then repairs DNA.
A PARP inhibitor competitively inhibits oxidative NAD when PARP recognizes oxidative NAD and repairs DNA, thereby exhibiting a pharmacological effect. That is, the PARP inhibitor inhibits PARP to cleave single-stranded DNA in tumor cells and to further cleave double-stranded DNA that is important for survival of the cells, leading to the death of the tumor cells.
In particular, in BRCA (Breast Cancer Susceptibility Gene)-mutant breast cancer, which is representative of hereditary breast cancer, inhibiting PARP which acts in the complement pathway of repair pathway of DNA leads to anti-tumor effect. In normal cells, even if PARP is inhibited, the cleavage of double-stranded DNA is repaired via the mechanism of repairing DNA by BRCA, resulting in no death of the cells. In contrast, in the tumor cells having BRCA mutation, the mechanism of repairing DNA does not act by the inhibition of PARP, and non-repaired single-stranded DNA accumulates in the cells, resulting in the cleavage of double-stranded DNA and the death of the tumor cells.
PARP plays an important role of the recognition of damage of DNA and the repairing it. Therefore, it is assumed that its inhibitor becomes an enhancer of the effect of anticancer agent having the effect of damaging DNA. With expectation of possibility of enhancing the effect by combining the PARP inhibitor with an anticancer agent such as temozolomide, carboplatin or gemcitabine, the treatment of cancers using PARP inhibitor has been currently developed.
The treatment of BRCA1- or BRCA2-mutant tumor by the combination of a PARP inhibitor, olaparib, with other anticancer agents (e.g. carboplatin and gemcitabine etc.) shows better results.
A rucaparib derivative, AG014699, which is a PARP inhibitor, is combined with temozolomide in the treatment of cancers, resulting in good tolerability and good anti-cancer effect.
Furthermore, the results of phase II clinical trial of combination of a PARP inhibitor, veliparib (ABT-888) with temozolomide shows that the combination exhibits the effect on metastatic breast cancer, and has good tolerability, suggesting that the combination may be a promising treatment method.
Patent Literature 1 discloses a polymeric compound to which a single drug having phenolic hydroxy group is bound. Patent Literature 2 discloses a polymeric compound to which a single drug having an alcoholic hydroxy group is bound. Patent Literature 3 and Non-Patent Literature 1 disclose the administration of the combination of a PARP inhibitor with a low-molecular anticancer agent such as temozolomide, carboplatin or gemcitabine, and a polymeric compound to which doxorubicin and other anticancer agents etc. are bound.
However, a polymeric compound in which camptothecin compound and an anti-cancer effect enhancer, for example, a PARP inhibitor are bound to a single molecule is not known.